Cerebellar and Basal Ganglia Markers Underlie Neuromotor Impairments in Adults with Autism Spectrum Disorder (ASD)

项目概要/摘要 虽然概念上是一种神经发育障碍，目前的研究主要集中在婴儿身上， 自闭症谱系障碍（ASD）越来越被认为是一种终身疾病， 可能对成人功能和生活质量产生不利影响。根据临床观察， 患有ASD的中老年人在衰老过程中可能特别易患神经变性疾病， 这些研究将验证小脑和基底神经节选择性地 在40至60岁的ASD成年人中被破坏。而且，这种破坏与神经运动障碍有关 和运动障碍的临床症状。游离水弥散磁共振成像（FWdMRI）将在 用于定量小脑小叶、齿状核和基底神经节核以及轴突的神经元变性 小脑脚的完整性，以确定这些皮质下靶点是否在ASD成人中被破坏 相对于年龄、性别和智商匹配的对照组。将使用精确抓握的功能MRI（fMRI）来量化 皮质-皮质下脑靶点的异常激活以及这些改变是否支持握力 ASD中与生产相关的损伤。使用神经运动测试敏感检测的变化， 小脑和基底神经节，我们将阐明在何种程度上表现Romberg的立场，快速的步骤， ASD成年患者的启动、坐立平衡和指向目标的手指指向功能受损。指导 强有力的初步数据，我们将追求三个具体目标：目标1）确定结构的变化， 小脑和基底神经节的FWdMRI。目的2）确定功能缺陷， 小脑和基底神经节的运动功能磁共振成像。目的3）确定神经运动损伤 自闭症的成年人。我们的团队是唯一有资格承担这一关键的R 01项目，因为它包括调查人员 在ASD的感觉运动神经生理学、ASD诊断、衰老和运动方面拥有专业知识和经验 MRI物理学和研究，以及生物统计学。这一建议是科学创新的，因为它将是 第一个系统地量化ASD中与年龄相关的神经运动问题，在大脑，行为和 临床领域。这个项目是重要的，因为它持有的承诺，以确定推定的非侵入性特征， 皮质下脑靶点有助于ASD中的衰老。如果成功，这项工作将识别新的大脑， 可以跟踪的生物行为目标，以了解，监测和治疗ASD中与衰老相关的疾病。

PROJECT SUMMARY/ABSTRACT Although conceptualized as a neurodevelopmental disorder with present research primarily focused on infants and children, autism spectrum disorder (ASD) has increasingly been recognized as a lifelong condition with the potential to have a detrimental impact on adult functioning and quality of life. Based on clinical observations that mid-to-older aged adults with ASD may be particularly susceptible to neurodegenerative diseases during aging, the proposed studies will test the central hypothesis that the cerebellum and basal ganglia are selectively disrupted in adults with ASD aged 40 to 60 years. And, this disruption is associated with neuromotor impairments and clinical signs of movement disorders. Free-water diffusion magnetic resonance imaging (FWdMRI) will be applied to quantify neuronal degeneration of the cerebellar lobules, dentate, and basal ganglia nuclei and axonal integrity of cerebellar peduncles to determine whether these subcortical targets are disrupted in adults with ASD relative to age-, sex-, and IQ-matched controls. Functional MRI (fMRI) of precision grip will be used to quantify abnormal activations of cortico-subcortical brain targets and whether these alterations underpin grip force production-related impairments in ASD. Using neuromotor tests sensitive in detecting alterations of the cerebellum and basal ganglia, we will clarify the extent to which performance of Romberg stances, quick step initiation, sit-to-stance balance, and goal-directed finger-pointing is compromised in adults with ASD. Guided by strong preliminary data, we will pursue three specific aims: Aim 1) Determine structural alterations in the cerebellum and basal ganglia in adults with ASD using FWdMRI. Aim 2) Determine functional deficits in the cerebellum and basal ganglia in adults with ASD using motor fMRI. Aim 3) Determine neuromotor impairments in adults with ASD. Our group is uniquely qualified to undertake this critical R01 project as it includes investigators with expertise and experience in sensorimotor neurophysiology in ASD, ASD diagnosis, aging and movement disorders, MRI physics and research, and biostatistics. This proposal is scientifically innovative as it will be the first to systematically quantify aging-related neuromotor issues in ASD at the levels of brain, behavioral, and clinical domains. This project is significant as it holds the promise to identify putative non-invasive traits of subcortical brain targets contributing to aging in ASD. If successful, this work will identify new brain and biobehavioral targets that can be tracked to understand, monitor, and treat aging-related conditions in ASD.